ABSTRACT ? CORE B The Transgenic and Geropathology Core, based at the University of Washington, will generate knockin or knockout mice for Project 2 using Crisper/Cas technology, carrying the variants identified in Project 1. Dr. Ladiges, in collaboration with Dr. Yousin Suh at Albert Einstein College of Medicine, has already generated a mouse strain carrying a rare variant in IGF-R1 identified by Project 1. Also, the Core will assist Project 1 in generating knockin or knockout cell lines for analysis of effects of the rare variants and miRNAs on growth, signaling and responses to stress. In addition, the Core will provide histopathologic analysis of tissue aging in the different mouse strains, for both Project 2 and Project 3, using an established Geropathology Grading Platform (GGP). The GGP is based on a standard set of guidelines, which have been developed to 1) detect the histological presence or absence of low impact lesions; and 2) determine the level of severity of high impact lesions in organs from aged mice. The platform is designed to generate a numerical score for each lesion in a specific organ, so that a total lesion score is obtained by adding each lesion score for that organ for one mouse. Total lesion scores are averaged between all mice in a specific cohort to obtain a composite lesion score (CLS) for that organ. The CLS will be used to investigate tissue effects of alterations in gene expression (Project 2), and compare responses to drug treatment over time (Project 3). The core is vital to the success of the projects and the overall success of the program.